POS0294 MITOCHONDRIAL DYSFUNCTION AND SENESCENCE OF NAÏVE T CELLS IN SJÖGREN´S SYNDROME
Authors: P. Javorova, J. Fessler, C. Rammerstorfer, M. Zeiler, A. S. Muralikrishnan, A. Lackner, J. Hermann, S. Zenz, J. Thiel, M. Stradner
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disorder characterized by lymphocytic infiltrations in exocrine glands. T-cells are considered major players in the pathogenesis of pSS. Previously, we reported premature aging and impaired homeostatic proliferation of pSS naïve CD4+ T-cells leading to peripheral lymphopenia [1]. Id3-deficient mice (Id3KO) develop a Sjögren's-like syndrome and are used as an animal model for pSS [2]. <h3>Objectives</h3> As mitochondrial function has been linked to premature aging and homeostasis of T cells, we assessed the mitochondrial status of T cells in pSS patients and the Id3KO mouse model of pSS. <h3>Methods</h3> Total immune cells were isolated from venous blood, lymph nodes and the spleens of Id3KO and wild type (WT) mice. Flow cytometric analysis was performed to characterize markers of cellular senescence p53, senescence-associated β-galactosidase (SA-β-GAL), and apoptotic rate in T-cell subsets. Staining with mitochondrion-selective fluorescent dyes MitoTracker Green, MitoTracker Deep Red, MitoSox Red was performed to assess mitochondrial mass, membrane potential (MtMP) and superoxide production, respectively. Similar analyses were performed on human T-cells from peripheral blood mononuclear cells of pSS patients and matched healthy individuals (HC). <h3>Results</h3> Similar to pSS patients, ID3KO mice show signs of pre-mature aging. The naïve cell compartment in CD4+ and CD8+ T-cells was significantly decreased in all studied tissues when compared to WT mice. Markers of cellular senescence, p53 and SA-β-GAL activity were increased in naïve CD4+ and CD8+ T cells. Apoptotic rate was also higher in Id3 KO T-cells. ID3 KO T-cells also exhibited a remarkable decrease of mitochondrial mass and MtMP. Despite having reduced mitochondrial mass and MtMP, we observed that Id3-deficient T-cells produced a higher amount of mitochondrial superoxide compared to WT mice. Again, naïve CD4+ T-cells were most affected by this increase. In line with our findings in ID3 KO mice, naïve CD4+ and CD8+ T-cells isolated from pSS patients produced significantly higher amounts of mitochondrial superoxide than those of HC. <h3>Conclusion</h3> In human pSS and mice with a pSS phenotype, naïve T cells are diminished and exhibit signs of pre-mature aging associated with significant accumulation of mitochondrial superoxide. ID3 KO mice may serve as a tool to test whether these changes are cause or consequence of pSS pathophysiology. <h3>References</h3> [1]Fessler J, Fasching P, Raicht A, Hammerl S, Weber J, Lackner A, et al. Lymphopenia in primary Sjögren's syndrome is associated with premature aging of naïve CD4+ T cells. Rheumatol (United Kingdom). 2021;60(2):588–97. [2]Rivera RR, Johns CP, Quan J, Johnson RS, Murre C. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, ld3. Immunity. 2000;12(1):17–26. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None declared.